Design and Construction of a Fully Functionalised Probe Library for Mode of Action Studies

The lack of novel drug targets is a barrier to the development of therapeutics for infectious diseases. In this paper the design and construction of a diverse set of small molecule fragments attached to functionalised linkers is discussed. The functionalised linkers are comprised of a diazirine photo crosslinking moiety alongside an acetylene group to facilitate target pulldown. These are designed to be probes to find new targets, though phenotypic screening, followed by cross coupling and pull-down of the target. They also have the potential to be used in screening programmes against whole cells, enzymes and receptors. To help reduce the number of false positives, a set of the fragments with an un-reactive acetamide has also been prepared, which will allow competition studies.